US1576014A - op cincinnati - Google Patents
op cincinnati Download PDFInfo
- Publication number
- US1576014A US1576014A US1576014DA US1576014A US 1576014 A US1576014 A US 1576014A US 1576014D A US1576014D A US 1576014DA US 1576014 A US1576014 A US 1576014A
- Authority
- US
- United States
- Prior art keywords
- urea
- ethyl isopropyl
- condensing
- temperature
- refluxing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 48
- 239000004202 carbamide Substances 0.000 description 26
- 238000004519 manufacturing process Methods 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- -1 ethyl isopropyl malonic ester Chemical compound 0.000 description 22
- 238000010992 reflux Methods 0.000 description 20
- 230000001476 alcoholic Effects 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 150000007656 barbituric acids Chemical class 0.000 description 12
- 238000009833 condensation Methods 0.000 description 10
- 230000005494 condensation Effects 0.000 description 10
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Diethyl malonate Chemical class CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 8
- HHLXJTDUHFBYAU-UHFFFAOYSA-N Probarbital Chemical compound CCC1(C(C)C)C(=O)NC(=O)NC1=O HHLXJTDUHFBYAU-UHFFFAOYSA-N 0.000 description 8
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- HNYOPLTXPVRDBG-UHFFFAOYSA-N Barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229960002713 calcium chloride Drugs 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 235000011148 calcium chloride Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000007799 cork Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 230000001624 sedative Effects 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- LAMBERT THORP OF CINCINNATI, OHIO, ASSIGNOR TO THE LAMBERT THOR]? COM- PANY, OF CINCINNATI, OHIO, A CORPORATION OF OHIO.
- the last step in one of the syntheses is that of condensing a derivative of malonic ester with urea.
- barbituric acid by condensing ethyl isopropyl malonic ester with urea in absolute alcoholic solution without establishing high pressure, such as would obtain in an autoclave without preliminary refluxing.
- 6. The process of manufacturing ethyl isopropyl barbituric acid by condensing ethyl isopropyl malonic ester with urea in absolute alcoholic solution at approximatt-rly atmospheric pressure without preliminary refluxing.
Description
Patented Mar. 9, 1926.
UNITED STATES 1,576,014 PATENT OFFICE.
LAMBERT THORP, OF CINCINNATI, OHIO, ASSIGNOR TO THE LAMBERT THOR]? COM- PANY, OF CINCINNATI, OHIO, A CORPORATION OF OHIO.
PROCESS OF MANUFACTURING BARBITURIC-ACID DERIVATIVES.
No Drawing.
To all whom it may cm'mern:
Be it known that I, LAMBERT Timur, a
' citizen of the United States of America, re-
- ing is a specification.
In the manufacture of 5-5 dialkyl derivatives of barbituric acid, several of whichare used in medicine as sedatives, the last step in one of the syntheses is that of condensing a derivative of malonic ester with urea.
These two substances unite by elimination of alcohol and a. corresponding derivative of barbituric acid results.
A number of patents issued both in this and other countries describe this condensation and the method of carrying it out, the usual custom being to bring about the condensation by treating molecular proportions of the malonic ester and urea in absolute alcoholic solution with sodium ethylate, and always, so far as applicant is aware, specifying that the use of an autoclave and 'superatmospheric pressure and high temperatures are necessary. Moreover, chemists would deem the use of an autoclave to be customary and necessary in carrying out this, and similar reactions. This method results often in low yields, due to artial destruction of the charge b the high temperature and pressure, an is also troublesome and time-consuming on account of the necessity of the slow and careful heating of the-equipment, care in controlling the temperature and pressure and in cooling the autoclave before it can be discharged.
I have now found that much of this trouble can be entirely eliminated and the use of an autoclave avoided by making the condensation at ordinary pressure in any suitable vessel, as follows, taking as a specific example the condensation of ethyl isopropyl malonic ester with urea:
In a 3 liter flask provided with reflux condenser, add absolute alcohol 900 00., in which is now dissolved metallic sodium 69 gm. When solution is complete, cool to 35 to 40 de ees C. and add urea (powdered) 100 In. Add a chip of porous plate and hang a w ite thread from the cork of the flask to the solution to h iilpl prevent superheating and bumping. 's reaction superheats and Application filed March 20, 1925. Serial No. 17,112.
bumps very violently and care should be exercised in carrying it out. Through the condenser is now added ethyl isopropyl malonic ester 250 gm. Turn the condenser down at an angle of 45 degrees and heat the flask in a calcium chloride bath of such a concentration that it boils at 115 degrees C. This should give an inside temperature of 107 degrees C. If not, the concentration of the cal-- cium chloride bath should be varied so that an inside temperature of 107 degrees C. is obtained. Maximum yields of the best product are obtained at approximately 10'. de-
grees C. If the temperature is right, distilloil alcohol until about 860 cc. have been collected. Some ammonia will come over with the alcohol. A solid mass of the sodium salt is left in the flask. it and filter f a clear solution is not obtained. Add hydrochloric acid until the mass'is acid to Congo paper. Filter, press out and resludge in water, and filter again so that the filtrates are free from mineral acid. The product is then recrystallized from hot water. Melting point of ethyl isopropyl. barbituric acid-197 degrees 0. uncorrected200 to 201 degrees C. corrected for stem exposure.
By this method, high yields of a superior product are obtained with practically no loss due to decomposition, and the operation may be carried out at maximum speed in simple equipment. Furthermore, there is no loss of time due to the necessity of controlling accurately pressures, as is required in the autoclave process. The method works on many other derivatives of malonic ester than that of the specific example given and I the process seems to be of general application.
It is to be emphasized that in carryin out this invention, one of the major considerations is that for maximum results the temperature of the reaction mass must be accurately controlled for the manufacture. of each derivative and that there is apparently a temperature best suited for the manufac- Add water to dissolve ture of each derivative, and in the specific example given, the temperature seems to be close to, if not exactly, 107 degrees C. at atmospheric pressure.
Owing to the fact that with other derivatives of malonic ester than the ethyl isopropyl compound, diflerent temperatures than that shown in the specific-example may be required for the broad application of this invention, I do not restrict myself to the temperature specified for the condensation, neither do I restrict myself to the exact volumes or proportionate weights of ingredients, since it may be necessary to vary these .0 et maximum results in specific instances.
aving described my invention, what I claim is:
l. The process of manufacturing barbituric acid derivatives by condensing malonic esters with urea in absolute alcoholic solution by means of metallic sodium by distilling the alcohol out of the mass without preliminary refluxing.
2. The process of manufacturing barbituric acid derivatives by condensing malonic esters with urea in absolute alcoholic solution by means of metallic sodium at atmos pheric pressure by distilling the alcohol out of the mass without preliminary refluxing.
3. The process of manufacturing barbituric acid derivatives by condensing malonic esters with urea in absolute alcoholic solu tion by means of sodium ethylate at a temperature of approximately 107 C. by distilling the alcohol out of the mass without preliminary refluxing.
4. The process of manufacturing ethyl isopropyl barbituric acid by condensing ethyl isopropyl malonic ester with urea in absolute alcoholic solution by means of sodium ethylate at atmospheric. pressure and at a temperature of approximately 107 C. by distilling the alcohol rapidly from the mass without preliminary refluxing.
5. The process of manufacturing ethyl absolute sodnnn ethylate as a condenslng agent, the
isopropyl. barbituric acid by condensing ethyl isopropyl malonic ester with urea in absolute alcoholic solution without establishing high pressure, such as would obtain in an autoclave without preliminary refluxing. 6. The process of manufacturing ethyl isopropyl barbituric acid by condensing ethyl isopropyl malonic ester with urea in absolute alcoholic solution at approximatt-rly atmospheric pressure without preliminary refluxing.
7. The process of manufacturing ethyl isopropyl barbituric acid by condensing ethyl isopropyl malonic ester with urea in alcoholic solution by means of operation being carried out at atmospheric pressure without preliminary refluxing.
8. The process of manufacturing ethyl isopropyl harbituric acid by condensing ethyl isopropyl malonic ester with urea in absolute alcoholic solution by means of sodium ethylate as a condensing agent, the operation being carried out at a pressure su'flicicntly low to render the use of an autoclave unnecessary without preliminary refluxing.
9. The process ot manufacturing ethyl isopropyl barbituric acid by condensing ethyl isopropyl .inalonic ester with-urea at atmospheric pressure at a temperature of approximately 107 degrees C. without preliminary refluxing.
This specification signed this 16th day of -March, 1925.
LAMBERT THORP.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US1576014A true US1576014A (en) | 1926-03-09 |
Family
ID=3410130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US1576014D Expired - Lifetime US1576014A (en) | op cincinnati |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US1576014A (en) |
-
0
- US US1576014D patent/US1576014A/en not_active Expired - Lifetime
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